Abstract 2659: Anti-HER3 antibody, HMBD-001, in combination with an EGFR inhibitor effectively inhibits tumor growth in biomarker-selected pre-clinical models of squamous cell carcinomas
Authors: Weiyi Toy, Dipti Thakkar, Khang Luu, Bui Ngoc Linh Chi, Jason Lai, Debleena Ray, Namita Gandhi, Alejandro Mas, Konrad Paszkiewicz, Piers Ingram, Jerome Boyd-Kirkup
Journal: Cancer Research (2023)

Abstract Squamous cell carcinomas (SCC) originate from stratified squamous epithelium in diverse anatomical locations that share common histological features and genetic mutations. Non-melanoma skin cancer, head and neck cancer (HNSCC), esophageal cancer (ESCC), and non-small cell lung cancer (sqNSCLC) make up the majority of SCC cases and together represent the largest subtype of cancer. There is a significant unmet need for effective treatment options post-progression of standard-of-care therapies. Alterations in receptor tyrosine kinase signaling pathways are commonly found in SCCs, e.g. EGFR is expressed in 90% of HNSCC, 76% of ESCC and 82% of sqNSCLC. However, the combination of EGFR targeting antibody cetuximab with chemotherapy confers limited clinical benefit and even initially sensitive tumors often develop resistance. Studies in SCC have implicated HER3, a key dimerization partner of HER family members, as one likely cause of treatment failure, through HER3 heterodimer activation of PI3K/AKT and MAPK/ERK pathways. In this study, we investigated the potential of combining HER3 and EGFR inhibitors to improve efficacy and overcome resistance. Previous attempts to target HER3 have shown limited clinical efficacy due to suboptimal HER3 inhibition, especially the lack of efficacy in ligand-independent activation mechanisms. They also lacked biomarker stratification for patients where HER3 inhibition would confer benefit. HMBD-001 is a clinical-stage anti-HER3 antibody which is being evaluated in a first-in-human, open-label, multi-center, dose escalation and expansion Phase I/IIa trial in patients with HER3 expressing advanced solid tumors (NCT05057013). HMBD-001 was rationally developed to uniquely block the HER3 heterodimerization interface to potently inhibit all HER3 dimer formation, including ligand-dependent and independent HER3 dimerization. Here, we show that dual blockade of EGFR and HER3 using cetuximab and HMBD-001 robustly inhibits tumor growth and is superior to either monotherapy. In multiple cell and patient derived SCC xenograft models, including models of HNSCC, ESCC and sqNSCLC, selected based on a novel gene signature that is robustly predictive of response, HMBD-001 in combination with cetuximab demonstrated up to 100% tumor growth inhibition and the abrogation of PI3K signalling. This combination was well tolerated with no relapse observed, even after a prolonged period of over 100 days in selected models. This study lays the foundation for testing HMBD-001 in combination with EGFR inhibitors in clinical settings. Better combination strategies of SoC and targeted therapeutics alongside a potent anti-HER3 mAb, in biomarker-selected patient populations, have the potential to meaningfully improve patient outcomes and prolong clinical benefit. Citation Format: Weiyi Toy, Dipti Thakkar, Khang Luu, Bui Ngoc Linh Chi, Jason Lai, Debleena Ray, Namita Gandhi, Alejandro Mas, Konrad Paszkiewicz, Piers Ingram, Jerome Boyd-Kirkup. Anti-HER3 antibody, HMBD-001, in combination with an EGFR inhibitor effectively inhibits tumor growth in biomarker-selected pre-clinical models of squamous cell carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2659.